Retinal ischemia occurs as a result of occlusion of a retinal blood vessel, such as occlusion of the central retinal vein or artery or a branch retinal vein or artery. Occlusion of blood vessels results in low oxygen tension in adjacent tissues, which triggers a signaling cascade that culminates in neovascularization, capillary nonperfusion and macular edema (Koroma et al., J. Cell. Biochem. 59: 123-132 (1995)). Retinal vein occlusion can occur in patients suffering from hypertension and hyperlipidemia and not infrequently can occur in diabetic patients, in particular patients suffering from type II diabetes. In type I diabetic patients, retinal vein occlusion and chronic hypoxia may be related to other microvascular complications of diabetes, such as diabetic retinopathy and proteinuria, although hypertension and a trend to increased hyperlipidemia are strikingly highly prevalent in diabetic patients with retinal vein occlusion (Dodson et al., European J. Ophthalmol. 3(3): 109-113 (1993)).
Tyrosine-phosphorylated proteins, vascular endothelial growth factor, and basic fibroblast growth factor increase after occlusion of a retinal blood vessel, especially within the occluded blood vessel. In addition, two signal proteins in tyrosine kinase pathways, namely phospholipase C.sub..gamma. and mitogen-activated protein kinase, are activated (Hayashi et al., Invest. Ophthalmol. Vis. Sci. 37(11): 2146-2156 (1996)).
Tyrosine phosphorylation of cellular proteins and changes in the expression of the fibroblast growth factor receptor have been suggested to play a role in the activation of endothelial cell proliferation by short-term hypoxia, such as that resulting from retinal blood vessel occlusion (Koroma et al. (1995), supra). Endothelial response can run the gamut from increased cell proliferation and synthesis of IL-1.alpha. (Shreeniwas et al., J. Clin Invest. 90: 2333-2339 (1992)) and upregulation of TGF.beta. (Santilli et al., Ann. Vasc. Surg. 5: 429-438 (1991)) to increases in glucose transporter (Loike et al., Am. J. Physiol. 263: C326-C333 (1992)), intracellular calcium (Arnould et al., J. Cell. Physiol. 152: 215-221 (1992)), prostaglandins (Michiels et al., Am. J. Physiol. 264: C866-C874 (1993)), membrane-associated proteins (Ogawa et al., Am. J. Physiol. 262: C546-554 (1992)), enthelin-1 (Gertler et al., J. Vasc. Surg. 18: 178-182 (1993)), and platelet aggregating factor (PAF; Caplan et al., Biochim. Biophy. Acta 1128: 205-210 (1992)). The origin of the endothelial cells can affect the manner in which they respond to hypoxia (Tretyahkov et al., Am. J. Physiol. 265: C770-780 (1993)). In this regard, hypoxia-induced phosphotyrosine has been shown to be markedly blocked by the protein tyrosine kinase inhibitors herbimycin-A and methyl 2,5-dihydroxycinnamate (Koroma et al. (1995), supra) but not by the protein tyrosine kinase inhibitor genistein (Koroma et al. (1995), supra).
Retinal ischemia is currently treated by retinal destruction, primarily by laser photocoagulation. The disadvantages of such treatment are obvious, with loss of visual function dependent on the extent of the retinal destruction required.
Ocular inflammation can occur as a result of disease, bacterial or viral infection, ocular surgery, which includes cataract surgery, retinal surgery, refractive surgery, and corneal surgery, e.g., corneal transplantation, and the like. Ocular inflammation can also occur as a result of corneal transplant rejection.
Cystoid macular edema is a common ocular abnormality resulting from a vast etiology and characterized by perturbation of the integrity of the blood-retinal barrier of the perifoveal capillaries and the optic nerve head. Such perturbation is readily observable as leakage of fluoresceine dye by angiography with accumulation of fluid as microcysts in the outer plexiform layer. Causative etiology includes postcataract or laser capsulotomy (Irvine-Gass syndrome), uveitis, branch or central vein occlusion, topical epinephrine use, severe hypertension, radiation retinopathy, perifoveal telangectasia and retinitis pigmentosa.
Ocular inflammation is currently treated by corticosteroids. The disadvantages of such treatment are cataracts, increased intraocular pressure, corneal melting, systemic complications, high blood pressure, aseptic necrosis of the femoral head, cardiovascular diseases, facial hair and many others. Nonsteroidal anti-inflammatory compounds are also administered. The disadvantages of such compounds include certain blood diseases, peptic ulcers, gastric distress, and platelet dysfunction with bleeding, and others.
Therefore, there remains a need for methods for the effective prophylactic and therapeutic treatment of retinal ischemia and ocular inflammation. Accordingly, it is a principal object of the present invention to provide a method of prophylactically and therapeutically treating retinal ischemia, such as that associated with occlusion of the central vein, the central artery, a branch vein or a branch artery, or macular edema following ocular surgery, such as cataract surgery, retinal surgery, refractive surgery, and corneal surgery, e.g., corneal transplantation, and the like. It is another principal object of the present invention to provide a method of prophylactically and therapeutically treating ocular inflammation. e.g., macular edema, such as that associated with disease, bacterial or viral infection, or ocular surgery, such as cataract surgery, retinal surgery, refractive surgery, and corneal surgery. e.g., corneal transplantation, and the like, and corneal transplant rejection, among others. These and other objects of the present invention will become apparent from the detailed description provided herein.